News and Publications

Neurologic Effects of Feline Immunodeficiency Virus

T.R. Phillips, M.C. Barr, R.A. Hart, J.N. Billaud, D. Selway, O. Billet, K. Walker, S. Choi, V. Hampton

Feline immunodeficiency virus (FIV) is a lentivirus of domestic cats. In addition to being an important feline pathogen, FIV is closely related to HIV, the agent that causes AIDS. Like HIV, FIV causes a chronic progressive immunodeficiency that ultimately results in the development of opportunistic infections and the death of the host. Neurologic abnormalities are a frequent complication of both viral infections. Our objectives are to gain a better understanding of the neuropathogenesis associated with FIV infections and to investigate various therapeutic interventions.

Using cultures of feline neurons, we investigated the potential of both FIV and its envelope protein to cause neuronal damage through the excitotoxicity mechanism. Neuronal swelling and release of lactate dehydrogenase were used to measure cellular damage. We also examined the effects of FIV envelope protein on increases in intracellular concentrations of calcium mediated by glutamate receptors.

Both FIV and its envelope protein significantly increased release of lactate dehydrogenase from cultured neurons. Neuronal swelling was detected in the cultures exposed to the virus but not in cultures exposed to saline, denatured virus, or the envelope protein alone. However, significant swelling occurred when both glutamate and the envelope protein from FIV-PPR, a molecular clone of the virus, were added to cultures. The general form of calcium signals mediated by N-methyl-d-aspartate receptors was similar in control neurons and in neurons exposed to the FIV-PPR envelope protein. However, treatment with the FIV-PPR envelope protein caused significant enhancement of the N-methyl-d-aspartate--induced calcium signal.

Our results indicate that both types of FIV envelope protein induce neurotoxic effects as shown by neuronal swelling and release of lactate dehydrogenase and that exposure of feline neurons to FIV envelope protein alters the handling of intracellular calcium. These findings help validate FIV infection in cats as a potential animal model for evaluating therapeutic approaches that target the excitotoxic mechanism of lentivirus-induced CNS disease.

Because astrocytes are essential in maintaining the homeostasis of the CNS, we determined the ability of FIV to infect feline astrocytes. We found that 2 molecular clones of the virus (FIV-34TF10 and FIV-PPR) produce a chronic low-level productive infection of feline astrocyte cultures. To investigate the consequences of this infection, we examined selected astrocyte functions. Infection with FIV-34TF10 significantly decreased the ability of astrocytes to scavenge extracellular glutamate. The effects of the infection did not appear to be a result of toxic reactions, but rather were more selective, because glucose uptake by the infected cultures was not altered.

Our data indicate that FIV productively infected feline astrocyte cultures at a low level and that this infection altered an important astroglial function. These new findings suggest that a chronic low-grade infection of astrocytes may impair the ability of the cells to maintain homeostasis of the CNS, and this impairment may, in turn, contribute to neurodegenerative effects often associated with lentivirus infections.

We are also investigating the lentivirus regulatory protein, FIV/Rev, and the effects of drugs of abuse on the progression of disease caused by FIV.

PUBLICATIONS

Barr, M.C., Phillips, T.R. Feline immunodeficiency virus. In: Textbook of Veterinary Internal Medicine, 4th ed. Ettinger, S.J. (Ed.). Saunders, Philadelphia, in press.

Billaud, J. N., Phillips, T.R. FIV: A lentivirus model for opiate effects on disease. In: Drugs of Abuse, Immunomodulation, and AIDS. Friedman, H., Madden, J., Klein, T. (Eds.). Plenum, New York, in press.

Gruol, D.L., Yu, N., Parsons, K.L., Billaud, J.N., Elder, J.H., Bloom, F.E., Phillips, T.R. Neurotoxic effects of feline immunodeficiency virus, FIV-PPR. J. Neurovirol., in press.

Phillips, T.R. Canine immune system. In: Encyclopedia of Immunology. Roitt, I.M., Delves, P.J. (Eds.). Adademic Press, San Diego, in press.

Yu, N., Billaud, J.N., Phillips, T.R. Effects of feline immunodeficiency virus on astrocyte glutamate uptake: Implications for lentivirus-induced central nervous system diseases. Proc. Natl. Acad. Sci. U.S.A. 95:2624, 1998.